Direct compression vehicle

ABSTRACT

An intimate, co-dried mixture of a major amount of tricalcium phosphate and a minor amount of locust bean gum is useful for the preparation of tablets by the direct compression technique. The mixture is blended with an active material and, if desired, fillers, disintegrating agents and lubricants, and the resulting blend is compressed without prior granulation or slugging to form a tablet containing at least about 10 weight per cent of the codried mixture.

' United States Patent 1 1111 3,900,569

Monti Aug. 19, 1975 [54] DIRECT COMPRESSION VEHICLE 3,424,842 H1969Nurnberg 424/94 3,627,583 12/1971 Troy et a]. 127/29 [75] inventor:Amhmy Irvmgton, 3,639,168 2 1972 Monti et al. 127 29 [73] Assignee:SuCrest Corporation, New York, 346391169 2/1972 BYOB; et 127/29 N Y3,821.414 6/1974 Monti 424/36l [22] Filed: Sept 1972 PrimaryExaminerShep K. Rose [21] A l. NO I 289,545 Attorney, Agent, orFirmKenyon & Kenyon Related U.S. Application Data [63]Continuatiomin-part of Ser. No. 185.344, Sept. 30, [57] ABSTRACT 332L414which is a continuation of An intimate, co-dried mixture of a majoramount of 885980 I969 abandoned tricalcium phosphate and a minor amountof locust bean gum is useful for the preparation of tablets by [52] U.S.Cl 424/3961; 424/363 the direct compression technique The mixture is [5I] 3/10 Alk 27/00 blended with an active material and, if desired,fillers, [58] Field of Search 424/358365 disintegrating agents andlubricants and the resulting blend is compressed without priorgranulation or slug- [56] References cued ging to form a tabletcontaining at least about 10 UNITED STATES PATENTS weight per cent ofthe co-dried mixture.

3 ()42 668 7/1962 Monti et al. 1. 260/209 3.134.719 5/1964 Sheth et al.424 229 4 Clams, N0 Drawmgs DIRECT COMPRESSION VEHICLE This applicationis a continuation-in-part of application Ser. No. 185,344, filed Sept.30, 1971, now US. Pat. No. 3,821,414 issued June 28, 1974, which in turnwas a continuation of application Ser. No. 885,980, filed Dec. 17, 1969,now abandoned.

This invention relates to direct compression vehicles. Moreparticularly, this invention relates to a particulate composition whichcan be admixed with an active material and, optionally, fillers,disintegrating agents and lubricants, and the resulting mixture directlycompressed into a tablet without the necessity of granulation orslugging of the mixture.

There are two general methods for forming tablets, i.e. compression of adry particulate material and trimration, or molding of a moist material,of which the first technique is by far the most frequently employed. Thecompression technique may be further subdivided into three majorcategories, viz. direct compression, wet granulation and drygranulation. The direct compression technique is the most desirable, inthat it employs the fewest steps and, in the case of the production oftablets containing sensitive or unstable actives, such as certainpharmaceuticals, minimizes the exposure to water or other conditionstending to adversely affect stability of the active. Unfortunately,however, it has been found that the direct compression technique is oflimited applicability.

First, most active materials possess poor compression properties, andthus are unsuited to this technique. In addition, many actives arerequired in such small amounts per unit dosage form that directcompression of the active alone is impractical, if not impossible. As aresult, the active must be admixed with a direct compression vehicle,i.e., an inert composition which is compatible with the active and hasgood compressibility. In addition, the direct compression vehicle shouldhave good flowability, good stability under normal ambient conditions,no adverse effect on tablet disintegration time, the ability to producegood tablet surfaces, and low cost.

To date, however, no material has been found which satisfies all ofthese criteria. For example, of the most popular of such compressionvehicles, spray-dried lactose possesses poor stability and discolors onstoring, dicalcium phosphate provides tablets having poor strength andhigh abrasiveness, and microcrystalline cellulose is expensive.

It is an object of the present invention to provide a new directcompression vehicle.

It is a further object of this invention to provide a direct compressionvehicle which may be combined with an active, and, if desired, fillers,disintegrating agents and lubricants, and the resulting dry mixturesubjected to direct compression.

The direct compression vehicles of the present invention are anintimate, co-dried admixture of a minor portion of locust bean gum and amajor portion of tricalcium phosphate. Neither locust bean gum nortricalcium phosphate is useful as a direct compression vehicle becauseneither can be compressed into a tablet of adequate strength. It issurprising then, that a co-dried mixture of these materials is souseful.

By the term major portion is meant a portion greater than about 50weight per cent, and by the term minor portion is meant a portion lessthan about 50 weight per cent. The minimum effective amount of lo- 2cust bean gum is not narrowly critical, provided that the resultingtablet has the desired strength characteristics, which also depend uponthe active component and other materials, e.g., fillers, disintegratingagents and lubricants, which may be incorporated with the codriedmixture which is compressed into the tablet. In general, however, thedirect compression vehicle of this invention should contain at leastabout 0.5 weight per cent, and preferably at least about 1 weight percent, locust bean gum. Tablet strength increases with increasingproportions of locust bean gum, but ordinarily amounts in excess ofabout 20 or 30 weight per cent are unnecessary. Higher proportions canbe employed, but there is no corresponding improvement in tabletstrength and, because locust bean gum is considerably more expensivethan tricalcium phosphate, are not desirable from an economicstandpoint. Amounts of locust bean gum in the range of from about 1 toabout 10 weight per cent are preferred, with an amount of about 5 weightpercent being particularly preferred.

The co-dried mixture is obtained by forming an aqueous suspension ordispersion of locust bean gumand tricalcium phosphate in the desiredproportions, drying the aqueous mixture and reducing the dried productto a particulate composition of the desired size.

To obtain the desired beneficial efiects, it has been found that a moreintimate mixture than that obtained by dry blending is necessary.Accordingly, the locust bean gum and tricalcium phosphate are mixed inan aqueous medium. The amount of water is not narrowly critical,provided that the resulting aqueous dispersion is sufficiently fluid topermit mixing. In general, this requires that there be at least 25 partswater per part 10- cust bean gum, with amounts of at least 50 partswater per part locust bean gum being preferred. The maximum amount ofwater is in no way critical, but amounts in excess of 200 parts per partof locust bean gum are unnecessary and only increase drying time and/orheat requirements and may preclude some drying techniques, such as drumdrying, which requires a relatively viscous liquid. In general, amountsof from about 50 to about 150 parts of water per part of locust bean gumare employed.

The water, locust bean gum and tricalcium phosphate can be combinedsimultaneously, or in any order. In a preferred technique, however,locust bean gum is added to the water and the resulting mixturethoroughly stirred to form a clear sol of hydrated gum in water. Thenthe tricalcium phosphate is stirred in. Because tricalcium phosphate isonly very slightly soluble in water, it is preferably added in a finelydivided form to ensure that it is uniformly dispersed throughout thelocust bean gum. In general, the particle size should be below aboutmesh, and particle sizes in the range of from about 200 to about 325mesh are preferred.

Drying of the resulting dispersion may be effected by a variety oftechniques, such as spray drying, tray drying, drum drying, and thelike.

The dried product is then broken up into particles having the desireddimensions and, if necessary, screened to achieve the proper size rangeand distribution. To ensure good flowability it is desired that theparticles be larger than mesh, and preferably be in the range of from 40to 80 mesh. The resulting particulate product comprises minute particlesof the tricalcium phosphate dispersed throughout a locust bean gummatrix, and is substantially different in appearance and properties frommixtures of the same dry materials 3 obtained by blending or the wetgranulation technique.

The particulate direct compression vehicle of this invention is admixedwith the active which it is desired to incorporate into tablet form and,if desired, other common tablet components such as fillers,disintegrating agents and lubricants, and the mixture is tabletted byknown direct compression procedures. The propor' tions of vehicle,actives, fillers, disintegrating agents and lubricants, are notcritical, and obviously depend upon the active material and the unitdose desired in the tablet, as well as the properties desired in thetablet. In general, however, the direct compression vehicle can compriseat least per cent of the tabletting mixture, and may comprise as much as99.9 per cent by weight, although amounts in the range of from about 30to about 95 per cent are more common.

By the term active material is meant any material intended for ingestionhaving a beneficial or desirable effect on the user. Suitable activematerials include therapeutic materials, such as anesthetics,antibiotics, antitussives, vitamins, aspirin, antacids, and the like;food stuffs, such as cocoa, dried oats, fruit flakes and the like;edible dyes and other food additives; and so on. The vehicle is afree-flowing granular material and imparts improved flow characteristicsto the active material and other components of the blend, therebyassuring ease of tabletting.

The blend of direct compression vehicle, active material and otheradditives is mixed and directly compressed to form a tablet employingconventional techniques and apparatus.

Although the co-dried mixture is useful as a direct compression vehicle,it has been found desirable to modify it by blending it with othermaterials prior to use as a direct compression vehicle.

For example, the co-dried composition can be diluted with granulartricalcium phosphate without serious reduction of tablet strength. Bythe term granular, as employed herein, is meant a product havingparticle sizes in excess of about 120 mesh, and preferably in excess of60 to 70 mesh. A suitable granular tricalcium phosphate is disclosed inU.S. Pat. No. 3,134,719. The amount of tricalcium phosphate employed isnot narrowly critical, but it should not be so high as to materiallyreduce the tablet strength afforded by the co-dried blend, and ingeneral the weight of granular tricalcium phosphate should not begreater than twice the weight of the co-dried blend.

Although the presence of tricalcium phosphate in amounts of up to about2 times the amount of co-dried blend does not materially affect tabletstrength, it has been found that as the proportion of co-dried blenddecreases the incidence of picking, i.e. the accumulation of material onthe die punch, increases. This can be minimized through the use oflubricants, such as magnesium stearate. However, as the amount oflubricant is increased above about 0.75 per cent, there is a seriousloss of tablet strength and the dispersibility of the resulting tabletin water is materially retarded. To minimize the need for lubricants,the co-dried blend can be admixed with locust bean gum, which tends toact both as a lubricating and as a disintegrating agent. The effectiveamount of locust bean gum is not highly critical, and ordinarily will beabout 5 to about weight per cent, based upon the co-dried blend. Whengranular tricalcium phosphate is present, the locust bean gum ordinarilywill be employed in an amount of from about 3 to about 7 per cent, basedupon the com- 4 bined weight of co-dried blend and granular tricalciumphosphate.

In some instances, the locust bean gum is unable to impart a desireddisintegration rate. In such cases, it has been found desirable toemploy a pharmaceutically acceptable acidic material as an auxilliarydisintegration agent. The combination of locust bean gum and acidicmaterial provides higher disintegration rates than are obtained witheither material alone. The acidic material can be an organic acid, suchas citric acid, 2- acetoxybenzoic acid, adipic acid, fumaric acid,succinic acid, malic acid or tartaric acid, with citric acid andtartaric acid being preferred, or it can be a salt of a weak base and astrong acid, such as ferrous sulfate, aluminium sulfate or monocalciumphosphate, with monocalcium phosphate being preferred. Citric acid isespecially preferred. The amount of acidic material is not highlycritical, provided it is sufficient to impart the desired disintegrationrate. In general, amounts of from about 1 to about 7 weight per cent,based upon codried blend, and from about 1 to about 3 weight per cent,based upon combined co-dried blend and granular tricalcium phosphatehave been found useful.

The acidic material can be admixed with the co-dried blend in anysuitable fashion. To assure uniform distribution, however, it has beenfound desirable to first admix the acidic material with a diluent,preferably tricalcium phosphate, and pulverize the mixture to form apowder, i.e. a particulate material having particle sizes of less than120 mesh, and preferably less than 150 to 250 mesh. The powder is thenadmixed with co-dried blend and, if employed, the granular tricalciumphosphate. The ratio of acidic material to diluent in the powder is nothighly critical, and approximately equal parts by weight (i.e. 40 to 60weight per cent acidic material and 60 to 40 weight per cent diluent)are satisfactory.

In accordance with this invention, a particularly preferred directcompression vehicle comprises a dry, physical admixture of:

a. From about 30 to about parts by weight of the co-dried mixture oflocust bean gum and tricalcium phosphate of this invention, as describedabove;

b. Up to about 60 parts by weight of granular tricalcium phosphate, thecombined weight of co-dried mixture and granular tricalcium phosphatebeing from about 90 to about parts by weight;

0. From about 3 to about 7 parts by weight of locust bean gum; and

d. From about 2 to about 5 parts by weight of a powdered blend ofapproximately equal parts by weight of tricalcium phosphate and anacidic material, especially citric acid.

The following examples are illustrative. Unless otherwise specified, allparts and percentages are by weight.

EXAMPLE I A lO-gram portion of locust bean gum was added to 1000 cc.water and the resulting mixture thoroughly stirred. Then 90 grams oftricalcium phosphate was added and thoroughly mixed to yield a creamywhite suspension. The suspension was drum dried to yield a free-flowingpowder, which was formed into a 13/32 inch, 0.5 gram tablet at 4500 psi.The ejection pressure needed to eject the tablets from the die was fromto psi and the Stokes hardness of the tablets was in excess of 45.

When disodium phosphate or calcium chloride were substituted for thetricalcium phosphate, tablets having a Stokes hardness of only 18 wereobtained.

EXAMPLE I] A 30-gram portion of locust bean gum was added to 1000 cc.water and stirred to form a viscous mixture. Then 70 grams of tricalciumphosphate was added, followed by 300 cc. and 200 cc. portions of water,with mixing to yield a homogenous milky suspension. After drum dryingand tabletting as described in Example I, the ejection pressure was 40psi and the Stokes hardness was 45.

EXAMPLE III Employing procedures similar to those described in Example1, except that the suspension was oven dried at 60C., compositionscontaining from to 7 weight per cent locust bean gum and 93 to 100weight per cent tricalcium phosphate were produced and formed intotablets. The Stokes hardness and dispersibi lity were measured and aresummarized as follows:

Tablet Composition, wt.% Product Properties Locust Bean Calcium GumPhosphate Hardness Dispersibility* 0 100 ll 15 min. 0 100 13 l 99 27 lmin.

95 43 3 min.

7 93 39 4% min. 7 93 37.5

Time to disperse in lo cc. of water in closed test tube which wasinverted at a rate of 30 times per minute.

6 From the above data it is evident that increased amounts of theco-dried blend afforded improved tablet strength and reduced theincidence of capping.

EXAMPLE V A mixture of 5 parts locust bean gum, parts tricalciumphosphate and parts of a co-dried mixture of tricalcium phosphate andlocust bean gum containing 3% locust bean gum was prepared and admixedwith magnesium stearate and varying amounts of citric acid. Theresulting tabletting mixtures were formed into tablets and thedisintegration time of the tablets was determined by the standard U.S.P.disintegration test. The data for these experiments are summarized asfollows:

Experiment No. 2 3

Mixture, 99 98 94 89 Magnesium stearate, l l l l Citric Acid, l 5 l0Disintegration time, min. 30 2% 1% 1% EXAMPLE VI A series of experimentswas performed in which codried locust bean gum-tricalcium phosphateblends were admixed with locust bean gum, magnesium stearate andmonocalcium phosphate, the mixtures were employed to form tablets, andthe tablets were evaluated for disintegration time. The data from theseexperiments are summarized as follows:

Run No. Mixture Composition 1 2 3 4 5 6 Blend A 1% locust bean gum),pts.100 Blend B (3% locust bean gum),pts. 100 Blend C (5% locust bean gum),ptsv I00 100 100 l00 Locust bean gum, pts. 5 5 5 5 5 5 Magnesiumstearate, pts. 1.5 1.5 1.5 1.5 1.5 L5 Monocalcium phosphate, pts. 5 5 5l0 15 20 Disintegration time, min. I 3 l0 l0 8 10 EXAMPLE IV A series oftabletting mixtures was prepared using 10- cust bean gum, tricalciumphosphate and two co-dried mixtures of locust bean gum and tricalciumphosphate containing 3 or 5% of locust bean gum. Each of the resultingmixtures was used to prepare l3/32-inch tablets on a Carver press at4500 pounds pressure for 10 seconds and the tablets were evaluated forStokes hardness and capping. The data for these experiments issummarized as follows:

Blend No. Component 1 2 3 4 Locust bean gum, 5 5 4.5 5 Tricalciumphosphate, 95 85 65.5 45 Co-dricd blend (3% locust 50 bean gum),Co-dn'ed blend (5% locust 10 30 bean gum), Stokes Hardness, kg 28.5 3L532.6 34.1 Capping Sev. Mod. None None Each of the direct compressionvehicles of the foregoing examples can be blended in accordance with thefollowing recipes and compressed to form tablets or wafers.

Other active ingredients of use in blends with the direct compressionvehicle are: sodium bicarbonate, acetanilid, phenecetin and magnesiumtrisilicate.

C. SPECIALTY PRODUCTS 1. INVERTASE TABLET 96.4 pts. direct compressionvehicle 3.6 pts. liquid triple strength invertase (I(=0.9) 1.0 pt.magnesium stearate 2. COCOA-SUGAR TABLET 35.0 pts. direct compressionvehicle 55.0 pts. agglomerated sugar 10.0 pts. high fat cocoa 0.2 pt.dendritic salt 1.0 pt. magnesium stearate After blending, the mixture istabletted to form a cocoa-sugar tablet.

3. HIGHLY CONCENTRATED COLOR TABLET 90.0 pts. direct compression vehicle10.0 pts. dried yellow FD&C No. 6

4. YEAST FOOD TABLET 34.0 pts. calcium sulfate (21-1 23.0 pts. flour9.0, pts. ammonium chloride 0.25 pt. potassium bromate 17.75 pts. sodiumdihydrogen phosphate 16.0 pts. salt 900.0 pts. direct compressionvehicle 10.1 pts. magnesium stearate What is claimed is:

l. A particulate composition useful as a direct compression vehicle forforming tablets consisting essentially of a dry mixture of:

a. about 100 parts by weight of an intimate co-dried blend of a minorbut effective portion of locust bean gum and a major portion oftricalcium phosphate;

b. up to about 200 parts of granular tricalcium phosphate;

c. locust bean gum as a lubricating agent and disintegrating agent in anamount of from about I to about 7 weight per cent, based upon saidco-dried blend, and from about 3 to about 7 weight per cent, based uponthe combined weight of said co-dried blend and granular tricalciumphosphate; and

d. a pharmaceutically-acceptable acidic material as an auxilliarydisintegrating agent in an amount of from about 1 to about 7 weight percent, based upon said co-dried blend, and from about 1 to about 3 weightper cent, based upon the combined weight of said co-dried blend andgranular tricalcium phosphate.

2. A composition according to claim 1 wherein said acidic material isselected from the group consisting of citric acid, 2-acetoxybenzoicacid, adipic acid, fumaric acid, succinic acid, malic acid, tartaricacid, ferrous sulfate, aluminum sulfate and monocalcium phosphate.

3. A composition according to claim 2 wherein said acidic material iscitric acid.

4. A particulate composition useful as a direct compression vehicle forforming tablets consisting essentially of:

a. from about 30 to about parts by weight of a particulate, intimateco-dried mixture of a minor but effective portion of locust bean gum anda major portion of tricalcium phosphate;

b. up to 60 parts by weight of granular tricalcium phosphate, thecombined weight of co-dried mixture and tricalcium phosphate being fromabout 90 to about parts by weight;

0. from about 3 to about 7 parts by weight of locust bean gum; and

d. from about 2 to about 5 parts by weight of a powdered blend ofapproximately equal parts by weight of citric acid and tricalciumphosphate.

1. A PARTICULATE COMPOSITION USEFUL AS A DIRECT COMPRESSION VEHICLE FORFORMING TABLETS CONSISTING ESSENTIALLY OF A DRY MIXTURE OF: A. ABOUT 100PARTS BY WEIGHT OF AN INTIMATE CO-DIRED BLEND OF A MINOR BUT EFFECTIVEPORTION OF LOCUST BEAM GUM AND A MAJOR PORTION OF TRICALCIUM PHOSPHATE,B. UP TO ABOUT 200 PARTS OF GRANULAR TRICALCIUM PHOSPHATE, C. LOCUSTBEAM GUM AS A LUBRICATING AGENT AND DISINTEGRATING AGENT IN AN AMOUNT OFFROM ABOUT 1 TO ABOUT 7 WEIGHT PER CENT, BASED UPON SAID CO-DIRED BLEND,AND FROM ABOUT 3 TO ABOUT 7 WEIGHT PER CENT, BASED UPON THE COBINEDWEIGHT OF SAID CO-DRIED BLEND AND GRANULAR TRICALCIUM PHOSPHATE, AND D.A PHARMACEUTICALLY-ACCEPTABLE ACIDIC MATERIAL AS AN AUXILLIARYDISINTEGRATING AGENT IN AN AMOUNT OF FROM ABOUT 1 TO ABOUT 7 WEIGHT PERCENT, BASED UPON SAID CO-DRIED BLEND, AND FROM ABOUT 1 TO ABOUT 3 WEIGHTPERCENT, BASED UPON THE COMBINED WEIGHT OF SAID CO-DRIED BLEND ANDGRANULAR TRICALCIUM PHOSPHATE.
 2. A composition according to claim 1wherein said acidic material is sElected from the group consisting ofcitric acid, 2-acetoxybenzoic acid, adipic acid, fumaric acid, succinicacid, malic acid, tartaric acid, ferrous sulfate, aluminum sulfate andmonocalcium phosphate.
 3. A composition according to claim 2 whereinsaid acidic material is citric acid.
 4. A particulate composition usefulas a direct compression vehicle for forming tablets consistingessentially of: a. from about 30 to about 90 parts by weight of aparticulate, intimate co-dried mixture of a minor but effective portionof locust bean gum and a major portion of tricalcium phosphate; b. up to60 parts by weight of granular tricalcium phosphate, the combined weightof co-dried mixture and tricalcium phosphate being from about 90 toabout 95 parts by weight; c. from about 3 to about 7 parts by weight oflocust bean gum; and d. from about 2 to about 5 parts by weight of apowdered blend of approximately equal parts by weight of citric acid andtricalcium phosphate.